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Showing papers in "Journal of Neural Transmission in 1990"


Journal ArticleDOI
TL;DR: The results indicate that dopamine receptor distribution is well preserved in the basal ganglia during evolution, although differences among species exist in their distribution outside the basal Ganglia and their absolute amount.
Abstract: Dopamine D 1 and D 2 receptor distributions were studied in the brain of the mouse, rat, guinea pig, cat and monkey by means of in vitro quantitative autoradiography using [3H]SCH 23390 and [3H]CV 205-502 to label D 1 and D 2 subtypes respectively. The distribution of both subtypes of receptors was similar within the basal ganglia of all species investigated. The highest densities for both subtypes were found in the nucleus caudatus, putamen, nucleus accumbens, olfactory tubercle and substantia nigra. Outside of the basal ganglia, differences in the distribution of both receptors were found among the species examined in regions such as cerebellum, cortex, hippocampus, superior colliculus and olfactory bulb. In all species D 1 receptor densities were higher than those of D 2. The absolute amount of both subtypes, however, varied among species. These results indicate that dopamine receptor distribution is well preserved in the basal ganglia during evolution, although differences among species exist in their distribution outside the basal ganglia and their absolute amount.

198 citations


Journal ArticleDOI
TL;DR: The existence of separate populations of dopamine receptors, differentially modulating cholinergic and glutamatergic synapses, suggests a possible resolution of the paradox of dopamine inhibition and reward-mediated learning.
Abstract: On the basis of behavioural evidence, dopamine is found to be involved in two higher-level functions of the brain: reward-mediated learning and motor activation. In these functions dopamine appears to mediate synaptic enhancement in the corticostriatal pathway. However, in electrophysiological studies, dopamine is often reported to inhibit corticostriatal transmission. These two effects of dopamine seem incompatible. The existence of separate populations of dopamine receptors, differentially modulating cholinergic and glutamatergic synapses, suggests a possible resolution to this paradox. The synaptic enhancement which occurs in reward-mediated learning may also be involved in dopamine-mediated motor activation. The logical form of reward-mediated learning imposes constraints on which mechanisms can be considered possible. Dopamine D1 receptors may mediate enhancement of corticostriatal synapses. On the other hand, dopamine D2 receptors on cholinergic terminals may mediate indirect, inhibitory effects of dopamine on striatal neurons.

140 citations


Journal ArticleDOI
TL;DR: Stereotypy is considered to represent an animal model of schizophrenia, and the antagonism of stereotypy with classical (haloperidol) as well as with atypical (clozapine) antipsychotic drugs is in accordance with the glutamate hypothesis of schizophrenia.
Abstract: MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclo-hepten-5, 10-imine hydrogen maleate], which blocks glutamatergic transmission at the NMDA-receptor-gated ion chanel, induced stereotypies which are similar to those found after intrastriatal injections of AP-5, e.g. sniffing and locomotion. Tests in familiar or unfamiliar environment (non-stressful or stressful situation) did not qualitatively change MK-801-induced effects. Haloperidol (0.1mg/kg, IP) delayed the onset and shortened the duration of MK-801 (0.16; 0.33mg/ kg, IP)-induced stereotypy whereas clozapine (5 mg/kg, SC) potently antagonized it. However, exact quantification of sniffing, measured in an experimental chamber designed for this purpose, revealed an antagonism by both drugs, haloperidol as well as clozapine. Stereotypy is considered to represent an animal model of schizophrenia, and the antagonism of stereotypy with classical (haloperidol) as well as with atypical (clozapine) antipsychotic drugs is in accordance with the glutamate hypothesis of schizophrenia.

138 citations


Journal ArticleDOI
TL;DR: Brain regional 5-hydroxytryptamine (5-HT) and/or 5-HIAA concentrations tended to be slightly higher in female rats than in males but differences were substantial only in the hippocampus where female values were 34% and 36% higher respectively, consistent with the synthesis rates of 5-HT as this was 53% greater in the female than in the male hippocampi.
Abstract: Brain regional 5-hydroxytryptamine (5-HT) and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations tended to be slightly higher in female rats than in males but differences were substantial only in the hippocampus where female values were 34% and 36% higher respectively. These findings were consistent with the synthesis rates of 5-HT as this was 53% greater in the female than in the male hippocampi. Other regions did not show significant sex differences. The 5-HT[n1A] agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 1 mg/kg sc) caused comparable decreases of 5-HT synthesis rate in both sexes and in all regions studied except the hippocampus where the percentage decrease was twice as large in the females (−64%) as in the males (−32%) so that the sex difference in 5-HT synthesis in this region largely disappeared. The results are discussed in relation to sex differences in behaviour and hippocampal function.

111 citations


Journal ArticleDOI
TL;DR: Comparison of the circadian variations in pineal adrenergic receptor numbers leads to the conclusion that the functional differences between rat and hamster pineal are probably not explicable in terms of the adrenergic receptors, but are caused most likely by (a) intracellular mechanism(s) beyond the Adrenergic receptors.
Abstract: Pineal adrenergic receptor numbers show circadian variations in both rat and Syrian hamster. In the rat pineal Β-adrenergic receptor density reaches peak values either late in the light phase or at middark; the differences in the circadian phase seem related to the light:dark cycle to which the animals are exposed. No circadian rhythm of pineal α-adrenergic receptors is documented in intact rats. In the Syrian hamster pineal Β-adrenergic receptor density is high throughout the light phase and drops to minimal values at the time of the nocturnal peak of melatonin production. The circadian rhythm of pineal α-adrenergic receptor numbers runs parallel to the Β-adrenergic receptor variation, but is less pronounced. In the rat, pineal melatonin production is rapidly induced by Β-adrenergic agonists at any time during a 24-hour period, even when the pinealocyte Β-adrenergic receptor number is lowest (early in the light phase). In contrast, the Syrian hamster pineal seems most responsive to Β-adrenergic agonists in the late night while being less responsive during the day when Β-adrenergic receptor density is high. Interestingly, the human pineal gland is also not especially responsive to adrenergic stimulation during the light phase, possibly making the Syrian hamster pineal a better model than the rat pineal for determining neural/pineal interactions in humans. Comparison of the circadian variations in pineal adrenergic receptors leads to the conclusion that the functional differences between rat and hamster pineal are probably not explicable in terms of the adrenergic receptors, but are caused most likely by (a) intracellular mechanism(s) beyond the adrenergic receptors.

77 citations


Journal ArticleDOI
TL;DR: The most consistent finding was a dose-related increase of both DA and DOPAC levels after treatment with NPY, which was reproduced by NPY13–36 in cortical tissue, whereas, in the sub-cortical regions, NPY 13–36 only reproduced the effects of NPY on the DOPac levels.
Abstract: The effects of centrally administered NPY on the brain monoamine systems were investigated in the rat. Neuropeptide Y (0.2-5.0 nmol), its C-terminal 13-36 amino acid (a.a.) fragment, NPY13-36 (0.4-10.0 nmol), or saline were injected into the right lateral cerebral ventricle of unrestrained rats. After 1 h the animals were decapitated, and the brains were taken out. Two cortical regions ('frontal' and 'parietal'), the striatum, the hypothalamus, and the brain stem were dissected out. The tissue contents of noradrenaline (NA), dopamine (DA) and serotonin (5-HT), as well as of their major metabolites, 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxy-indole acetic acid (5-HIAA) were measured. The most consistent finding was a dose-related increase of both DA and DOPAC levels after treatment with NPY. This effect was reproduced by NPY13-36 in cortical tissue, whereas, in the sub-cortical regions, NPY13-36 only reproduced the effects of NPY on the DOPAC levels. Less consistent effects were found on the NA systems, in which NA levels showed a tendency to increase following low, and decrease after high doses of NPY. These effects were largely reproduced by NPY13-36. In addition, NPY increased tissue levels of MHPG in frontal cortical tissue in a dose-related manner. The brain 5-HT systems were not affected.

75 citations


Journal ArticleDOI
TL;DR: Dissociation of the effects of 5- HT and 8-OH-DPAT on forebrain 5-HT synthesis after local application into the dorsal or the median raphe strongly supports the contention of heterogeniety in the brain 5-ht receptor population in terms of receptor subtypes and/or receptor regulation.
Abstract: 5-HT (10 and 40 micrograms) and 8-OH-DPAT (1 and 5 micrograms) were locally applied into the dorsal or median raphe nuclei in awake, unrestrained, rats. All animals were also treated with the 5-HTP and DOPA decarboxylase inhibitor NSD-1015, 100 mg kg-1 SC, 30 min before decapitation. 5-HT or 8-OH-DPAT were administered 5 min before NSD-1015. The regional brain in vivo rate of tyrosine and tryptophan hydroxylase activity was estimated by measuring the accumulation of DOPA and 5-HTP. The following brain regions were sampled: neocortex, hippocampus, dorso-lateral neostriatum, ventro-medial neostriatum, nucleus accumbens, olfactory tubercle, globus pallidus, septum and the amygdala. Compared to normal controls, there were small and inconsistent effects on forebrain 5-HTP accumulation by saline injections into the dorsal or the median raphe (an increase in 3 out of 36 experiments), whereas strong effects by the injection procedure were noted on forebrain DOPA accumulation (an increase in 15 out of 36 experiments). Injections of 5-HT (same effect by 10 or 40 micrograms) into the dorsal raphe, produced a decrease in 5-HTP accumulation in all forebrain areas except for the hippocampus and the septum, whereas no effects were seen in any area after median raphe injections. In contrast, 8-OH-DPAT preferentially produced a decrease in forebrain 5-HTP accumulation after median raphe injections and less, but statistically significant effects by dorsal raphe injections. The 8-OH-DPAT injection into the median raphe primarily affected limbic forebrain areas (hippocampus, nucleus accumbens, ventro-medial neostriatum, amygdala and the septum). This dissociation of the effects of 5-HT and 8-OH-DPAT on forebrain 5-HT synthesis after local application into the dorsal or the median raphe strongly supports the contention of heterogeniety in the brain 5-HT receptor population in terms of receptor subtypes and/or receptor regulation.

73 citations


Journal ArticleDOI
TL;DR: The results indicate a subsensitive (presynaptic) 5-HT1A receptor and/or a defective post-receptor signalling pathway in depression and are consistent with the hypothesis that 5- HT1A receptors are down-regulted during AMI treatment.
Abstract: Hypothermic responses to 5-HT1A receptor activation by the selective ligand ipsapirone (IPS) were attenuated in depressed patients as compared to controls. Chronic treatment with amitriptyline (AMI) further impaired 5-HT1Amediated hypothermia. The results indicate a subsensitive (presynaptic) 5-HT1A receptor and/or a defective post-receptor signalling pathway in depression and are consistent with the hypothesis that 5-HT1A receptors are down-regulted during AMI treatment.

72 citations


Journal ArticleDOI
TL;DR: The results suggest that enhanced activity of the mesoprefrontal DA neurons renders these DA neurons much more dependent up on tyrosine availability for maintenance of transmitter output.
Abstract: Mesocortical dopamine (DA) neurons projecting to the prefrontal and cingulate cortices possess a faster basal firing rate and exhibit more bursting than other midbrain DA neurons. Thus, we examined whether tyrosine administration could preferentially affect DA synthesis in these DA neurons. Tyrosine administered at doses as low as 25 mg/kg significantly increased in vivo tyrosine hydroxylation in the prefrontal and cingulate cortices without affecting it in other mesocortical, mesolimbic, and nigrostriatal DA terminal fields examined. Further studies in the mesoprefrontal DA neurons showed that tyrosine administered at higher doses of 50 mg/kg initially enhanced tyrosine hydroxylation and elevated endogenous DA levels within 60 min. The resultant increases in DA levels appeared to feedback and normalize prefrontal tyrosine hydroxylase activity. The levels of DA metabolites in the prefrontal cortex were unaltered by doses of tyrosine from 25–200 mg/kg, suggesting that the functional transmitter outflow from these DA neurons is not normally affected by precursor administration under resting conditions. However, when these mesocortical DA neurons were pharmacologically activated following administration of the anxiogenic Β-carboline, FG 7142, tyrosine administration (25 mg/kg) was effective in increasing DA metabolite levels in the prefrontal cortex. These results thus suggest that enhanced activity of the mesoprefrontal DA neurons renders these DA neurons much more dependent up on tyrosine availability for maintenance of transmitter output.

68 citations


Journal ArticleDOI
TL;DR: In case of patients with cancer anorexia a significant rise of the ratio in plasma between free and tryptophan/large neutral amino acids, competing with tryPTophan for its brain entry, was observed, suggesting a specific role of the serotoninergic system in the pathogenesis of cancerAnorexia.
Abstract: Eighteen untreated cancer patients and ten sex- and age-matched healthy volunteers were studied. In all patients eating behavior was investigated by means of a specific questionnaire from which the presence of anorexia and anorexia-related symptoms was assessed. To investigate the role of tryptophan in cancer anorexia, fasting plasma and CSF levels of tryptophan and other neutral amino acids were assayed in patients and controls. Cancer patients showed abnormally high plasma free tryptophan levels. In case of patients with cancer anorexia a significant rise of the ratio in plasma between free and tryptophan/large neutral amino acids, competing with tryptophan for its brain entry, was observed. This increase was correlated to a consistent rise of CSF tryptophan levels suggesting a specific role of the serotoninergic system in the pathogenesis of cancer anorexia.

68 citations


Journal ArticleDOI
TL;DR: The absence of salsolinol in the urine of one subject after Madopar administration seems to indicate that the biological system(s) involved in the reduction of the C = N bond in 1,2-dehydrosalsol can be missing or not, or poorly, functional in some individuals, and suggests that there is no alternative pathway for the formation of salolinol for healthy volunteers.
Abstract: The R enantiomer of salsolinol was detected in the urine of two out of six healthy subjects, whereas 1,2-dehydrosalsolinol was present in the urine of all the subjects. (S)-salsolinol was never detected. Administration of Madopar for 7 days resulted in the presence of large amounts of (R)- and (S)-salsolinol in the urine of five out of the six subjects, the urinary excretion of 1,2-dehydrosalsolinol being generally not markedly increased.

Journal ArticleDOI
TL;DR: Data suggest that persisting alterations in receptor binding are primarily seen in dopamine D2 and GABA receptors after withdrawal from chronic administration of haloperidol but not the atypical neuroleptics, clozapine and raclopride.
Abstract: Rats were administered haloperidol, clozapine, raclopride, or no drug for 28 days or 8 months. Following a 3 week withdrawal period, in vitro autoradiography was utilized to examine receptor binding for dopamine D2 ([3H]spiperone and [3H]raclopride), dopamine D1 ([3H]SCH23390), GABAA ([3H]muscimol), benzodiazepine ([3H]RO15-1788), and muscarinic ACh receptors ([3H]QNB). [3H]spiperone was elevated in striatal subregions only in haloperidol-treated rats, with the largest increases seen in the 8 month duration animals. Striatal [3H]raclopride binding was increased after both short- and long-term treatment in both haloperidol and raclopride, but not clozapinetreated animals. Clozapine-treated rats showed significant increases in [3H]SCH23390 in the nucleus accumbens after 28-day administration; otherwise no changes were seen for this ligand in any other groups. Increases in [3H]muscimol binding in the substantia nigra reticulata were seen in haloperidol-treated rats after 8 month treatment. Binding of [3H]QNB and [3H]RO15-1788 were not significantly different from control for any of the drug-treated groups. These data suggest that persisting alterations in receptor binding are primarily seen in dopamine D2 and GABA receptors after withdrawal from chronic administration of haloperidol but not the atypical neuroleptics, clozapine and raclopride.

Journal ArticleDOI
TL;DR: Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione, and TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/ kg did not modify the pattern ofSIH at all.
Abstract: 8-OH-DPAT (2.5–10 mg/kg) and buspirone (10 mg/kg) but not 5,7DHT (200 Μg/mouse), pCPA (75 and 150 mg/kg, three times), ritanserin (0.1 and 0.2 mg/kg), LY 53857 (1.5 and 3 mg/kg), GR 38032 F (0.1–100 Μg/kg), TFMPP (5 and 20 mg/kg) and mCPP (2.5 and 5 mg/kg) antagonized the rise in body temperature that occurs to the last mice removed from their group housing, which was termed as stress-induced hyperthermia (SIH). Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione. Instead, when cerebral 5-HT content was reduced to 50% by 5,7-DHT-induced lesion, the effect of buspirone on SIH was decreased. TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/kg did not modify the pattern of SIH at all. The lower dose of TFMPP evoked a hyperthermic and the higher a hypothermic response.

Journal ArticleDOI
TL;DR: The combined influence of semistarvation and hyperactivity on central catecholamine turnover in the rat is discussed as an animal model for the effects of malnutrition and heavy exercise often observed in anorexia nervosa.
Abstract: Male Wistar rats were housed in running wheel cages and were restricted in their food intake, in order to reduce the initial body weight by 30% within 10 days. Rats increased their daily running up to distances between 7 and 11 km compared to the maximum 2.5 km in controls fed ad libitum. The hypothalamic noradrenaline (NE) turnover, as estimated by the concentration of the major metabolite MHPG, was significantly decreased in semistarved sedentary rats compared to controls. Hyperactivity resulted in marked elevation of NE turnover at all time points examined. Semistarvation-induced decreases of dopamine (DA) turnover as estimated by the concentrations of its major metabolite DOPAC, could also be compensated by hyperactivity. The circadian pattern of NE turnover parallels the pattern of running activity. MHPG levels at times of high activity were even higher than in controls fed ad libitum (p<0.01). The availability of the precursor tyrosine, as indicated by the ratio of plasma tyrosine to the large neutral amino acids, was significantly decreased in semistarvation (p<0.0001); hyperactivity caused a further decrease (p<0.001), indicating that tyrosine availability is not, under these conditions, a limiting factor for noradrenaline turnover. The combined influence of semistarvation and hyperactivity on central catecholamine turnover in the rat is discussed as an animal model for the effects of malnutrition and heavy exercise often observed in anorexia nervosa.

Journal ArticleDOI
TL;DR: The findings show that spinal mechanisms are highly stereoselective toward nicotine, and suggest that primarily nicotinergic andalpha-adrenergic receptors are involved in its central antinociceptive effects.
Abstract: Spinalized rats received an intrathecal injection of either (−)-nicotine or (+)-nicotine in order to study the stereoselectivity of antinociception. Pain threshold was measured using the tail-flick test. Both stereoisomers had antinociceptive effects, but (−)-nicotine was up to 970 times more potent, depending on test conditions. The antinociceptive action of (−)-nicotine was antagonized by mecamylamine and yohimbine but not by naloxone and atropine. The findings show that spinal mechanisms are highly stereoselective toward nicotine, and suggest that primarily nicotinergic andalpha-adrenergic receptors are involved in its central antinociceptive effects.

Journal ArticleDOI
TL;DR: The lack in difference in k3 values between TD patients, neuroleptic treated patients without TD and control subjects throws doubt on the hypothesis that changes in striatal D2 dopamin receptor number or binding affinity is an etiological mechanism for persistent TD.
Abstract: Dopamine D2 receptor binding characteristics were studied by positron emission tomography (PET) using N-11C-methyl spiperone as receptor ligand in patients on longterm treatment with neuroleptic drugs and in control subjects. Eight of the patients had symptoms of tardive dyskinesia whereas three patients did not have any symptoms. Control subjects comprised 5 healthy volunteers and 7 patients with pituitary tumors. All patients had been free of neuroleptic drugs for at least 4 weeks. The time dependent regional radioactivity in the striatum was measured and the receptor binding rate, k3, proportional to receptor number, Bmax and association rate for the receptor was calculated in relation to the cerebellum. The lack in difference in k3 values between TD patients, neuroleptic treated patients without TD and control subjects throws doubt on the hypothesis that changes in striatal D2 dopamin receptor number or binding affinity is an etiological mechanism for persistent TD.

Journal ArticleDOI
TL;DR: Data on medicated patients demonstrate that the average values of most of the above parameters indicate the decreased number of available D2-receptors whereby, besides an age dependent decline, the caudate-to-cerebellum ratio affords the relatively best distinction among diagnostic groups.
Abstract: PET studies of dopamine D2-receptor binding were performed in thirty patients with various disorders related to the dopaminergic system and in six healthy controls. Uptake of [18F]fluoroethylspiperone in caudate over three hours was analyzed in terms of several indices of receptor binding:caudate-to-cerebellum activity ratio, concentration of ligand as percentage of injected dose, caudate-to-blood radioactivity ratio, slope of tracer uptake curves, binding potential, kinetic constants of a three compartment model. In 14 patients brain glucose metabolism was also measured. Data on medicated patients demonstrate that the average values of most of the above parameters indicate the decreased number of available D2-receptors whereby, besides an age dependent decline, the caudate-to-cerebellum ratio affords the relatively best distinction among diagnostic groups. In individual cases, large variability among subjects permits only the classification of severe pathologies. Morphological damage and neuronal loss in the striatum may also cause abnormal low values both for the indices of receptor binding and for glucose consumption, thus providing a possible pathogenetic link between receptor dysfunction and impaired energy metabolism.

Journal ArticleDOI
TL;DR: Naltrexone HCl decreased these latencies and enhanced the seizures significantly, providing further evidence for the existence of a tonic anticonvulsant opioid system in the brain.
Abstract: The effects of a pharmacological blockade of the mu opiate receptors on the manifestation of tonic-clonic seizures were investigated in freely moving animals. 4-aminopyridine, a specific blocker of the neuronal K+ channels was used to produce generalized convulsions. After pretreatment of adult rats with 1 mg/kg naltrexone HCl, 3, 5, 7, 9, 14 mg/kg 4-aminopyridine was injected intraperitoneally, and the latencies of the symptoms generated by 4-aminopyridine were measured. Naltrexone HCl decreased these latencies and enhanced the seizures significantly. The experiments provided further evidence for the existence of a tonic anticonvulsant opioid system in the brain.

Journal ArticleDOI
TL;DR: Volumetry of the parahippocampal gyrus was performed applying stereological methods and no difference was found comparing 18 schizophrenic brains with 18 sex- and age-matched controls.
Abstract: Volumetry of the parahippocampal gyrus was performed applying stereological methods. No difference was found comparing 18 schizophrenic brains with 18 sex- and age-matched controls. Variable sulcal pattern may contribute to inconsistency with previous findings.

Journal ArticleDOI
TL;DR: Data demonstrate that ischemia in the dorsal hippocampus is associated with a mared release of DA and NE, which may contribute to the selective vulnerability of the lateral hippocampus to neuronal damage during ischemIA.
Abstract: The cerebral dialysis technique was employed to monitor extracellular concentrations of dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the dorsal hippocampus of gerbils before and after cerebral ischemia induced by carotid artery occlusion. Extracellular concentrations of DA and NE in the dorsal hippocampus increased from baseline levels of <35 fmol/collection interval to 180 and 200 fmol/collection, respectively, within 36 minutes following carotid artery ligation (n=8 animals). Extracellular concentrations of the DA metabolites, DOPAC and HVA, did not change significantly following carotid artery ligation. These data demonstrate that ischemia in the dorsal hippocampus is associated with a mared release of DA and NE. This release may contribute to the selective vulnerability of the dorsal hippocampus to neuronal damage during ischemia.

Journal ArticleDOI
TL;DR: In this article, the specificity of the antibodies was controled by immunostaining and by a competition test between lectins (Concanavalin A-Con A- and wheat germ agglutinin-WGA-) and antibodies (A74 IgG).
Abstract: Antibodies were raised in rabbit against crude subcommissural organ (SCO) extract of 19 day old chick embryos. After absorption with crude brain extract, the IgG fraction was purified by ion exchange chromatography. The specificity of the antibodies was controled by immunostaining and by a competition test between lectins (Concanavalin A-Con A- and wheat germ agglutinin-WGA-) and antibodies (A74 IgG).

Journal ArticleDOI
Jørn Arnt1, John Hyttel1
TL;DR: The results suggest that DA D-2 agonists can be ranked according to gradually increasing agonist efficacies rather than classified into autoreceptorselective versus nonselective D- 2 agonists.
Abstract: The effects of the dopamine (DA) D-2 antagonist YM 09151-2 and the DA D-2 agonists terguride, preclamol, EMD 23448, B-HT 920, quinpirole and (−)-NPA were studied in a battery of behavioural tests in order to evaluate their relative efficacies. Furthermore, their affinities for DA D-2 receptors labelled by3H-N-0437 were measured in vitro. All agonists reduced spontaneous locomotor activity and induced marked contralateral circling behaviour in 6-hydroxy-DA-lesioned rats. Quinpirole and (−)-NPA increased motor activity after high doses. YM 09151-2 did not induce circling. In hemitransected rats quinpirole and (−)-NPA had weak effects when given alone, whereas the other agonists were ineffective. After combination with DA D-1 agonist SK&F 38393, B-HT 920 became effective, and the effects of quinpirole and (−)-NPA were facilitated. EMD 23448, preclamol and terguride were not active. In contrast, the two latter compounds fully inhibited the response to apomorphine. In stereotypy experiments a similar activity pattern was observed. Finally, drug discrimination studies showed that quinpirole, (−)-NPA and B-HT 920 substituted for the stimulus effects induced by d-amphetamine or (−)-NPA in different groups of rats. EMD 23448 induced intermediate effects, whereas preclamol and terguride had weak effects. None of the partial agonists inhibited the response of d-amphetamine. YM 09151-2 potently inhibited the effect of d-amphetamine.

Journal ArticleDOI
TL;DR: A study of the acute effects of isatin, an endogenous MAO inhibitor related to tribulin, on rat brain serotonergic function was undertaken and there was a trend for the number of3H-ketanserin binding sites was to be decreased.
Abstract: A study of the acute effects of isatin, an endogenous MAO inhibitor related to tribulin, on rat brain serotonergic function was undertaken. A single dose of isatin significantly increased 5-HT concentrations in the hypothalamus and cortex but did not significantly alter 5-HIAA concentrations. Synaptosomal 5-HT uptake was unaffected but there was a trend for the number of 3H-ketanserin binding sites was to be decreased. The results of the study are discussed in terms of the relationship of isatin to tribulin and their possible causal role in stress.

Journal ArticleDOI
TL;DR: It is demonstrated that melatonin secretion from rat pineal glands may be elicited through a VIPergic system which is independent of the well-known noradrenergic system.
Abstract: The rat pineal gland is known to release melatonin in response to noradrenergic stimulation. The effect of vasoactive intestinal peptide (VIP), one of the neuropeptides present in the pineal, was examined on perifused rat pineal glands. VIP stimulated melatonin release with a dose-dependent effect above 10−7 M. In regard of kinetic characteristics, the pattern of melatonin release after VIP stimulation was similar to that after isoproterenol stimulation. 10−6 M VIP-stimulated melatonin release was not altered when the pineal glands were treated with 10−5 M propranolol (a β-adrenergic antagonist) or 10−5 M prazosin (an α1-adrenergic antagonist). Thus VIP has a noradrenergic-independent effect on melatonin secretion. Conversely, this VIP effect is greatly inhibited by the specific action of a VIPergic antagonist. This suggests that VIP acts on melatonin synthesis through its own binding sites.

Journal ArticleDOI
TL;DR: While tryptophan administration can stimulate serotonin production in primate brain, the effect may be restricted to certain brain regions, and it is suggested that the transport of the large neutral amino acids into brain occurs via a competitive mechanism similar to that for other mammals.
Abstract: Plasma and brain levels of tryptophan and other large neutral amino acids, and brain levels of serotonin and 5-hydroxyindoleacetic acid (5 HIAA) were measured in groups of adult cynomolgus monkeys 1 hr after they ingested one of four doses of a tryptophan-carbohydrate mixture. The doses had been administered once daily for 13 weeks. Dose-related increments occurred in plasma tryptophan, the plasma ratio of tryptophan to the sum of other large neutral amino acids, and in brain tryptophan levels. In contrast, the plasma ratios and brain levels of the other neutral amino acids each declined. Serotonin and 5 HIAA levels increased significantly, and in, a dose-related manner in the brainstem and striatum, but not in cortex or hypothalamus. The results suggest that while tryptophan administration can stimulate serotonin production in primate brain, the effect may be restricted to certain brain regions. They also suggest that the transport of the large neutral amino acids into brain occurs via a competitive mechanism similar to that for other mammals.

Journal ArticleDOI
TL;DR: The level of Gi/Go was significantly decreased by 42% in the putamen of the left hemisphere in schizophrenics; caudate head and globus pallidus levels were unchanged.
Abstract: We detected the existence of Gi (the inhibitory G-protein) or Go (a similar G-protein of unknown function) in the striatum of control and schizophrenic brains utilizing pertussis toxin-catalyzed ADP ribosylation. The level of Gi/Go was significantly decreased by 42% in the putamen of the left hemisphere in schizophrenics; caudate head and globus pallidus levels were unchanged. Decreased Gi or Go may underlie enhanced dopamine function in the schizophrenic brain.

Journal ArticleDOI
TL;DR: There may be quantitative differences in the plasma concentration of endogenous factors that affect 5-HT uptake between patients with premenstrual syndrome and control subjects and that such differences may explain the previously reported alteration of platelet 5- HT uptake and content associated with PMS symptoms.
Abstract: The effects of plasma and an aqueous plasma fraction from patients with premenstrual syndrome (PMS) and control subjects on the uptake of 5-hydroxytryptamine (5-HT) in washed human platelets and rat forebrain synaptosomes were studied. Pre- and postmenstrual samples of unextracted plasma from the control group significantly enhanced platelet uptake of 5-HT. In contrast, an aqueous fraction following extraction of the plasma with organic solvents caused a dose-dependent decrease of 5-HT uptake. Plasma obtained from patients with PMS caused less stimulation of 5-HT uptake compared to plasma from the control group. The aqueous fraction of premenstrual plasma from patients tended to inhibit 5-HT uptake to a greater extent than a similar plasma fraction from controls. The inhibition of 5-HT uptake was associated with an increase in Km. Aqueous plasma fractions from both groups also inhibited 5-HT uptake in brain synaptosomes. However, there were no significant differences between groups. The results of the platelet study suggest that there may be quantitative differences in the plasma concentration of endogenous factors that affect 5-HT uptake between patients with PMS and control subjects and that such differences may explain the previously reported alteration of platelet 5-HT uptake and content associated with PMS symptoms.

Journal ArticleDOI
TL;DR: The effect of lithium on the PFH could be related to the improvement of the autonomic and cyclic symptoms of patients with manic depressive disorders undergoing lithium therapy.
Abstract: Chronic administration of lithium displays therapeutic and prophylactic effects in bipolar affective disorders, but its mechanism of action remains unknown. Several studies in animals and humans strongly suggest that central serotonergic neurons might be involved in lithium effects. In the experiments reported here microdialysis with removable probes and high pressure liquid chromatography and electrochemical detection were used to assess the amphetamine-induced release of serotonin (5-HT) and the 5-hydroxy-indoleacetic acid (5-HIAA) levels in the perifornical hypothalamus (PFH) and hippocampus (HP) of freely moving rats before and after chronic lithium chloride administration (2 meq/kg, as intragastric daily injections for 14 days). The serum lithium levels were 0.66 ± 0.08 meq/1. After lithium treatment, the amphetamine-induced 5-HT release was significantly enhanced in the PFH but not so in the HP. Basal levels of 5-HIAA in the control group decreased but remained unchanged in the lithium group in the PFH. No change of basal levels of 5-HIAA was observed in the HP. The effect of lithium on the PFH could be related to the improvement of the autonomic and cyclic symptoms of patients with manic depressive disorders undergoing lithium therapy.

Journal ArticleDOI
TL;DR: It is demonstrated that pentobarbital perfusion either before or following the onset of ischemia inhibits extracellualr release of dopamine in the striatum, which may, in part, be responsible for the protective effect of pentobarBital in ischemic brain injury.
Abstract: We examined whether pentobarbital (PB) inhibited the acute extracellular release of dopamine that occurs in the striatum following the onset of ischemic injury in the gerbil model of stroke. The cerebral dialysis technique was employed to monitor striatal extracellular dopamine concentrations before and after carotid artery occlusion while perfusing either a control solution of artificial cerebrospinal fluid (CSF) or a 1 mM solution of pentobarbital in CSF (PB/CSF). During perfusion with CSF, extracellular dopamine increased from a baseline concentration of 0.40±0.09 (SEM) pmoles/10 minute collection interval to 30.0± 9.0 pmoles/10 minutes after carotid artery occlusion. In contrast, during perfusion with PB/CSF, dopamine levels increased from a baseline of 1.37±0.3 pmoles/10 minutes to 8.30±2.6 pmoles/10 minutes; this increase was significantly less than the increase in controls. In animals with established ischemia, repeatedly alternating the perfusion fluid between CSF and PB/CSF demonstrated that dopamine concentrations were significantly increased with CSF alone and decreased with PB/CSF. These findings demonstrate that pentobarbital perfusion either before or following the onset of ischemia inhibits extracellualr release of dopamine in the striatum. Inhibition of neurotransmitter release may, in part, be responsible for the protective effect of pentobarbital in ischemic brain injury.

Journal ArticleDOI
I. Miyai1, S. Ueno1, Shiro Yorifuji1, Harutoshi Fujimura1, Seiichiro Tarui1 
TL;DR: Results imply regulation of nAChR transcripts by cell to cell interactions and may provide supporting evidence for the occurrence of supersensitivity in deafferentated cholinergic neurons.
Abstract: We investigated the effect of a unilateral lesion of the nucleus basalis magnocellularis (nbm) on the expression of nicotinic acetylcholine receptors (nAChRs) in the rat cerebral cortex. Cortical nAChR concentration as determined by [3H]nicotine binding was unaffected by the nbm lesion. Expression levels of nAChR subunit mRNAs were measured using cDNA clones coding for the receptor subunits, alpha-3, alpha-4, and beta-2. At 1 week postlesion, expression levels of alpha-4, and beta-2 were increased by an average of 82% and 19%, respectively. On the other hand, expression levels of these mRNAs on the lesioned side 4 weeks after lesioning did not differ from those on the control side. Expression of alpha-3 was not altered by the nbm lesion. These results imply regulation of nAChR transcripts by cell to cell interactions. Coincrease of alpha-4 and beta-2 transcripts may provide supporting evidence for the occurrence of supersensitivity in deafferentated cholinergic neurons.